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The Journal of Nutrition Vol. 128 No. 12 December 1998,
pp. 2324-2333
,,,
* Laboratoire de Pharmacologie et Physiopathologie Cellulaires, Université Louis Pasteur de Strasbourg, CNRS ERS 653 Faculté de Pharmacie, BP 24, 67401 Illkirch-Cedex, France and Laboratoire de Pharmacognosie, Université Louis Pasteur de Strasbourg, CNRS GDR 1206 Faculté de Pharmacie, BP 24, 67401 Illkirch-Cedex, France
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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This study investigated the possible active principles which support the endothelial nitric oxide-dependent relaxation produced by red wine and other plant polyphenolic compounds in thoracic aorta from male Wistar rats (12-14 wk old). Relaxation experiments were recorded isometrically on vessels precontracted with norepinephrine. Ten different chromatographic fractions (3-18 mg) isolated from red wine polyphenolic compounds (RWPC) and some available defined polyphenols (10-15 mg) were tested. Fractions enriched into either anthocyanins or oligomeric condensed tannins exhibited endothelium-dependent vasorelaxant activity (maximal relaxation in the range of 59-77%) comparable to the original RWPC. However, polymeric condensed tannins elicited a weaker vasorelaxant activity than the original RWPC (maximal relaxation ranged between 20-47%, P < 0.01). Moreover, the representative of either phenolic acid derivatives (benzoic acid, vanillic acid, gallic acid), hydroxycinnamic acid (p-coumaric acid, caffeic acid) or the flavanol [(+)-epicatechin] classes failed to induce this type of response. Among the anthocyanins, delphinidin (maximal relaxation being 89%), but not malvidin or cyanidin, showed endothelium-dependent vasorelaxation. These results show that anthocyanins and oligomeric-condensed tannins exhibited a pharmacological profile comparable to the original RWPC. These compounds may be involved in the reduction of cardiovascular mortality related to the presence of wine, fruits and vegetables in the diet.
KEY WORDS: polyphenols · tannins · anthocyanins · nitric oxide · vasorelaxation
The vascular endothelium lies at the interface between the circulating blood cells and the vascular smooth muscle cells, responds to flow and shear stress and to vasoactive stimuli, and plays a crucial role in regulating blood flow and vascular tone (Furchgott and Vanhoutte 1989 Many plants, including grapes, contain extractable compounds that cause endothelium-dependent vasorelaxation in vitro (Fitzpatrick et al. 1993 Recently, we reported that low concentrations of a red wine extract enriched in polyphenolic compounds (RWPC) from 10
The aim of the present investigation was to determine which group(s) of polyphenols is able to cause endothelium-dependent vasorelaxation. RWPC was chromatographically resolved into 10 fractions in order to separate the two major groups of polyphenols that they contain: polymerized flavanols and anthocyanins. The endothelium-dependent and -independent relaxing effects of these fractions were compared to those of commercially available polyphenols.
The RWPC dry powder from red wine (Cabernet-Sauvignon grape variety) was provided by Dr. M. Moutounet (Institut National de la Recherche Agronomique, Montpellier, France). Briefly, the procedure involved three steps: 1) adsorption of phenolics on a preparative column, 2) alcoholic desorption and 3) gentle evaporation of the alcoholic-eluent. The concentrated residue was finely sprayed to obtain the RWPC dry powder. One liter of red wine produced 1.3 g of RWPC, which contained 100 mg/g of total catechins plus proanthocyanidins expressed as catechin (with only 1.0% of each monomeric form of catechin and epicatechin), 64 mg/g of total anthocyanins (including 36% of malvidin-3-glucoside), 5 mg/g of total flavonols and 8.7 mg/g of total phenolic acids (including 19.5% of caftaric acid). Acetylcholine, benzoic acid, caffeic acid, (+)-epicatechin, gallic acid, N Chromatographic resolution
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
, Vane et al. 1990). In addition, vascular endothelium can synthesize and release different relaxant factors such as nitric oxide (NO),4 prostanoid derivatives and the so called endothelium-derived hyperpolarizing factor (Vanhoutte 1989). The release of these substances produces endothelium-dependent vasorelaxation of different vascular beds from different species including rat aorta (Rapoport and Murad 1983). In many vascular pathologies, such as hypertension, diabetes and atherosclerosis, endothelium-dependent vasorelaxation to different vasodilator agonists is reduced (Hongo et al. 1988, Koga et al. 1989, Taddei et al. 1995). One of the mechanisms accounting for this dysfunction of the endothelium is a decreased release of NO (Barton et al. 1997, Gryglewski et al. 1986). Thus, endothelial NO plays an important role in regulating the vascular tone both in humans and animals under physiological and pathophysiological status.
and 1995). This is also the case for red wine (Andriambeloson et al. 1997, Fitzpatrick et al. 1993). Epidemiological studies have suggested that dietary factors, including red wine consumption, might explain the lower incidence of coronary heart diseases in the French population (the "French paradox") despite high saturated fat consumption (Renaud and De Lorgeril 1992, Ulbricht and Southgate 1991). However, the dietary plant compounds that might protect against cardiovascular diseases are still unknown.
5 to 102 g/L elicited enhanced NO generation, cyclic guanosine 3', 5-monophosphate accumulation and endothelium-dependent relaxation in rat aortic rings (Andriambeloson et al. 1997). Polyphenols include a large number of compounds (Fig. 1). Much attention has been paid to flavonoids, because of their antioxidant properties, which result in decreased generation of oxidized lipids, might be involved in cardioprotective mechanisms (Teissedre et al. 1996). However, in our experiments, endothelium-dependent vasorelaxation produced by RWPC did not result from protection of NO against oxidative breakdown. Also, it has been known for many years that some flavonoids like quercetin produce vasorelaxation and inhibit platelet aggregation, perhaps as a result of cyclic nucleotide phosphodiesterase inhibition (Beretz et al. 1978 and 1982, Duarte et al. 1993). This mechanism may be involved in endothelium-independent vasorelaxation related to a direct action on smooth muscle cells caused by RWPC at high concentration. Furthermore, quercetin-induced vasorelaxation was endothelium-independent, although quercetin has antioxidant properties (Duarte et al. 1993, Fitzpatrick et al. 1993).
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Fig 1.
Structures of phenolic and polyphenolic compounds. Example of condensed tannins: structure of procyanidin oligomeric B-type. RH or H, with n = 0, 1, 2, 3, 4, 5.
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Fig 2.
TLC-fingerprint of the RWPC fractions. (A) TLC-fingerprint of fractions 1-7 (F1-F7) and reference compounds such as leucocianidol (Le) corresponding to a mixture of oligomeric condensed tannins, (+)catechin [(+)Ca] and ( 
)epicatechin [()Ep] as examples of monomeric flavan-3-ols. F1-F3 displayed purple zone between Rf 0.25 and 0.5, characteristic of high polymerized tannins. Leucocianidol displayed two bands and traces with lower Rf (<0.3) and three bands at Rf = 0.35, 0.40 and 0.60 corresponding to tetra-, tri- and monomeric forms, respectively. The F4-F7 displayed brown-colored bands characteristic of oligomeric condensed tannins, like those of Le. The monomer flavanol-3-ols reference compounds, (+)Ca and ()Ep, occur at Rf = 0.6. Note that in this elution condition, the fraction enriched into anthocyanins (like for example F8) does not migrate. (B) TLC-fingerprint of anthocyanin-enriched fractions, fractions 8-10 (F8-F10), and reference compounds such as cyanidin (Cy) (Rf = 0.8) and delphinidin (De) (Rf = 0.65) as anthocyanin aglycones and cyanidin-3-glucoside (Cy3) (Rf = 0.5) as anthocyanin monoglycoside. F8 corresponds to anthocyanin diglycosides (Rf = 0.4-0.55). Fraction 9 consists mainly of anthocyanin monoglycoside (Rf = 0.35, like that of reference compound cyanidin-3-glucoside). Fraction 10 is enriched into anthocyanin aglycones (Rf = 0.8 and 0.65, like those of the standard cyanidin and delphinidin, respectively).
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Fig 3.
Concentration-response curves for high polymeric condensed tannin fractions in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium. Values are means ± SEM of three experiments.
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Fig 4.
Concentration-response curves for oligomeric condensed tannin fractions in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium. Values are means ± SEM of two to four experiments. **P < 0.01, *P < 0.05 indicate the significant difference between curves with and without functional endothelium assessed by ANOVA.
View this table:
Table 1.
Vasorelaxation produced by red wine polyphenolic compounds in rat aortic rings with functional endothelium
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Fig 5.
Concentration-response curves for anthocyanin fractions in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium. Values are means ± SEM of two to three experiments. **P < 0.01 indicates the significant difference between curves with and without functional endothelium assessed by ANOVA.
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Fig 6.
Concentration-response curves for phenolic acid derivatives in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium. Values are means ± SEM of three experiments. **P < 0.01 indicates the significant difference between curves with and without functional endothelium assessed by ANOVA.
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Fig 7.
Concentration-response curves for hydroxycinnamic acid derivatives (A and B) and for (+)-epicatechin (C) in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium. Values are means ± SEM of three experiments.
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Fig 8.
Concentration-response curves for anthocyanins in norepinephrine precontracted rat thoracic aortic rings with or without functional endothelium, or with functional endothelium in the presence of L-NAME (300 µmol/L). Values are means ± SEM of three to five experiments. **P < 0.01 indicates the significant differences versus curves with functional endothelium assessed by ANOVA.
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
-L-arginine-methyl ester (L-NAME), norepinephrine, p-coumaric acid and vanillic acid were purchased from Sigma Chemical (Grenoble, France). Cyanidin chloride, malvidin chloride and delphinidin chloride were from Extrasynthese (Genay, France). Leucocianidol was a generous gift from Laboratoire Pharmafarm (Courbevoie, France).
). The successive fractions were analyzed by TLC (Silica gel 60 F254, Merck, Nogent sur Marne, France; system A: toluene-acetone-formic acid, 3:3:1, with vanillin-sulfuric acid reagent; system B: ethyl acetate-glacial acetic acid-formic acid-water, 100:11:11:26, without any chemical treatment), UV and visible spectroscopy. They were combined according to their TLC profiles (Rf and color) and absorbances at 280 and 520 nm (Da Silva et al. 1991, Wagner 1996). They were classified as fraction 1 (1-200 mL), fraction 2 (201-400 mL), fraction 3 (401-600 mL), fraction 4 (610-970 mL), fraction 5 (980-1030 mL), fraction 6 (1040-1200 mL), fraction 7 (1210-2600 mL), fraction 8 (2610-4000 mL), fraction 9 (4010-6000 mL), fraction 10 (6010-9000 mL). They were separately concentrated under reduced pressure using centrifugal evaporator (RC10-22, Jouan, Paris, France), weighted and then frozen.
Organ bath experiments
Aortic preparations and mounting. Male Wistar rats (12-14 wk old) bred in our institute from strains provided by Iffa Credo (Abresle, France) were killed by cervical dislocation and then exsanguinated by carotid artery transection. Thoracic aorta was removed and carefully cleaned of adhering fat and connective tissue and cut into rings (2-3 mm length). The rings with or without functional endothelium were then mounted on standard organ bath filled with a physiologic salt solution (PSS) (composition in mmol/L: NaCl, 119; KCl, 4.7; CaCl2, 1.25; MgSO4, 1.17; KH2PO4, 1.18; NaHCO3, 25; glucose, 11), maintained at 37°C and continuously bubbled with a 95% O2-5% CO2 mixture. The endothelium was removed by gentle rubbing of the intima of ring with curved forceps. Indeed, aortic rings without functional endothelium were used to test the direct action of different polyphenols on vascular smooth muscle but not endothelial cells. Resting tension was adjusted to 2 g. Tension was measured with an isometric force transducer.
Experimental protocols.
After washing and returning to baseline tension, aortic rings with and without endothelium were precontracted with norepinephrine (i.e., 80% of maximal response obtained in vessels with functional endothelium) using 0.3 or 0.1 µmol/L norepinephrine, respectively. When the contraction reached a steady state, increasing doses of polyphenolic compounds (105-3 · 101 g/L) corresponding to 8.9 · 108-2.6 · 103 mol/L as benzoic acid equivalent, to 6.0 · 108-1.8 · 103 mol/L as p-coumaric acid equivalent, to 3.4 · 108-1.0 · 103 mol/L as catechin equivalent and to 3.0 · 108-0.9 · 103 mol/L as malvidin equivalent were added cumulatively. Four different polyphenolic compounds were tested in each aorta from each rat. The aorta was cut in eight rings divided into two groups with and without functional endothelium.
Statistics
Since the aorta were precontracted to the same extent with norepinephrine whether the endothelium was present (2.98 ± 0.10, n = 32) or not (3.02 ± 0.08, n = 30), the relaxations were expressed as percentages of the level of precontraction. The sensitivity of vessels to each fraction was expressed as the pD2 value (i.e., the negative logarithm of the concentration of fraction required to produce 50% of the maximal relaxation). All results are expressed as mean ± SEM of n experiments. Student's unpaired t test was used for statistical analysis of pD2. ANOVA was used to compare the concentration-response curves to polyphenols between groups with and without functional endothelium. A P value level of 0.05 or less was considered significant.| |
RESULTS |
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Abstract
Introduction
Methods
Results
Discussion
References
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RWPC fractionation.
TLC-fingerprints shown in Figure 2 correspond to tannin fractions eluted in system A (Fig. 2A) and anthocyanin fractions eluted in system B (Fig. 2B). Each fraction can be identified by comparison of its Rf value and color with previously published data (Da Silva et al. 1991, Delcour et al. 1981, Wagner and Bladt 1996).
). An unidentified weak spot in higher Rf values (>0.6) is also observed.
), corresponding to oligomeric condensed tannins comparable with the standard leucocianidol (Fig. 2A). Fraction 4 consisted mainly of monomeric flavanol-3-ols, comparable with the authentic (+)catechin and ()epicatechin (Rf = 0.6) shown in Fig. 2A. Fraction 5 contained monomeric (Rf = 0.6) and dimeric (Rf = 0.45) forms, while fraction 6 contained mainly dimeric forms. Fraction 7 contains more condensed tannin forms like trimers or tetramers (Rf = 0.4 and 0.45, respectively).
). They correspond to anthocyanin diglycosides (Rf = 0.4-0.55) for the fraction 8. The fraction 9 consists mainly to anthocyanin monoglycosides (Rf = 0.35, comparable with reference compound cyanidin-3-glucoside). The fraction 10 is enriched into anthocyanin aglycones (Rf = 0.8 and 0.65, comparable with the standards cyanidin and delphinidin, respectively) (Fig. 2B).
Endothelium-dependent vasorelaxing activity of fractions Fractions 1-3 produced moderate vasorelaxation, at relatively high concentrations (Fig. 3). However, there was no significant difference between the results obtained in aortic rings with and without functional endothelium, indicating that the influence of endothelium was weak, if present at all. The maximal effect of these fractions was significantly lower than that of RWPC. These fractions were identified as high polymeric condensed tannins with size >1500.
Vasorelaxant activity of defined polyphenols. Among the tested defined polyphenols, phenolic acid derivatives (Fig. 6), hydroxycinnamic acids (Fig. 7A and B), flavanols (Fig. 7C) and anthocyanins (Fig. 8), only the anthocyanin delphinidin (Fig. 8C) elicited the endothelium-dependent vasorelaxation. This effect was inhibited by L-NAME, suggesting the involvement of NO. The pD2 value of delphinidin was 1.50 ± 0.57, and its Emax was 83.86 ± 4.87%. By comparison with RWPC (Table 1), delphinidin was therefore slightly but significantly (P < 0.05) less potent, but its maximal effect was not different. The molar concentration of delphinidin producing half maximal relaxation was nevertheless 26.30 ± 0.41 µmol/L, showing that this compound is relatively potent.
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DISCUSSION |
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Abstract
Introduction
Methods
Results
Discussion
References
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In the present study, we found that oligomeric condensed tannins and anthocyanins displayed similar endothelium-dependent vasorelaxant properties as the original RWPC extract. Also, only the anthocyanin delphinidin showed the same pharmacological profile as RWPC, among all the tested defined polyphenols.
, Paganga and Rice-Evans 1997, Timberlake 1981). This complexity is the main difficulty in identification of the active compounds among dietary polyphenols. This study used a chromatography technique which allowed us to separate polymeric or oligomeric condensed tannins and anthocyanins according to both their molecular size and their adsorption properties. Each fraction was characterized using both thin layer chromatography and spectroscopy. Using these techniques, polyphenols from RWPC could be resolved according to their chromatographic behavior, although their precise identification and quantification remains to be determined.
) produced endothelium-independent vasorelaxation only at high concentrations. In this respect, both compounds only share the pharmacological property of high concentration of RWPC. They may produce relaxation through mechanisms such as inhibition of muscle cells protein kinase C, inhibition of cyclic nucleotide phophodiesterases (Beretz et al. 1978 and 1980, Duarte et al. 1993) or decreased Ca2+ uptake in smooth muscle cells, as previously reported by the group of Duarte in the same preparation (Duarte et al. 1993, Herrera et al. 1996).
).
). These differential pharmacological activities of condensed tannins might be due to the difference in the chemical composition of these compounds for a given molecular weight (Fig. 1). We cannot distinguish among these possibilities.
).
. The three tested anthocyanins differed in their structure by the number and state of methoxylation of the hydroxyl substituents. Thus, these results indicate that, among anthocyanins, only some specific structures are able to cause endothelium-dependent vasorelaxation. As delphinidin produced a maximal effect comparable with that of RWPC, but was less potent, it is likely that RWPC contains other more potent polyphenol(s) producing comparable endothelium-dependent vasorelaxation.
, Hertog et al. 1992 and 1993, Künhau 1976) that can also mediate endothelium-dependent vasorelaxation. In addition, polyphenols are detected in human plasma from nonsupplemented humans at individual levels in the range of 0.5-1.6 µmol/L (Paganga and Rice-Evans 1997), a concentration comparable to the EC50 (concentration required to produce 50% of the maximal relaxation comprised between 1-10 µmol/L) of active fractions, suggesting that the concentrations of these compounds can be reached in the plasma and hence might act on the endothelium in vivo. We suggest that one of the mechanisms of the cardioprotective effects of fruits, vegetables or wine might be the increase in endothelial NO production induced by polyphenols present in all these foods, i.e., oligomeric condensed tannins and anthocyanins.
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FOOTNOTES |
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-L-arginine-methyl ester; NO, nitric oxide; pD2, negative logarithm of concentration (g/L) of fraction required to produce 50% of the maximal relaxation; PSS, physiologic salt solution; Rf, retention frontal; RWPC, red wine polyphenolic compounds.
Manuscript received 8 May 1998. Initial reviews completed 1 July 1998. Revision accepted 17 August 1998.
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ACKNOWLEDGMENTS |
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We thank M. Moutounet for the gift of RWPC. The authors express gratitude to M. C. Martinez for critical reading of the manuscript and D. Wagner and C. Untereiner for technical assistance.
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Abstract
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Methods
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References
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